Palladium-catalyzed intramolecular coupling of amino-tethered vinyl halides with ketones, esters, and nitriles using potassium phenoxide as the base

Article abstract of DOI:10.1002/adsc.200404148

Vinyl halides undergo intramolecular coupling with amino-tethered ketones, esters, and nitriles in the presence of a palladium catalyst and potassium phenoxide as the base. This reaction constitutes a useful methodology for the synthesis of monocyclic, br

Full text of DOI:10.1002/adsc.200404148

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Palladium-Catalyzed Intramolecular Coupling of Amino-Tethered
Vinyl Halides with Ketones, Esters, and Nitriles Using Potassium
Phenoxide as the Base
´
Daniel Sole,* Xavier Urbaneja, Josep Bonjoch
`
`
Laboratori de Química Organica, Facultat de Farmacia, Universitat de Barcelona, 08028-Barcelona, Spain
Fax: (þ34)-93-402-4539, e-mail: dsole@ub.edu
Received May 27, 2004; Accepted: September 15, 2004
SupportingInformation for this article is available on the WWW under http://asc.wiley-vch.de.
Abstract: Vinyl halides undergo intramolecular cou-
plingwith amino-tethered ketones, esters, and ni-
triles in the presence of a palladium catalyst and po-
tassium phenoxide as the base. This reaction consti-
tutes a useful methodology for the synthesis of mono-
cyclic, bridged, and spirocyclic nitrogen-containing
compounds.
In our previous work, we established that the use of
Pd(PPh3)4 (0.2 equivs.) and KO-t-Bu (1.5 equivs.) in
THF at reflux effectively promotes the intramolecular
couplingof amino-tethered vinyl halides and ketones
to afford bridged, condensed, and monocyclic nitro-
gen-containing compounds.[4] However, for some sub-
strates side reactions such as the elimination of HX lead-
ingto alkynes which may undergo subsequent coupling
with the startingvinyl halides to afford dimeric com-
pounds, and dealkylation at the nitrogen, resulted in
low or moderate yields of the cyclization products.[4b]
As these side reactions can mainly be attributed to the
use of a strongbase, a more general protocol for the in-
tramolecular a-alkenylation of ketones could be found
if, instead of KO-t-Bu, a milder base was used. In this
context, it should be noted that the intramolecular cou-
Keywords: alkenylation; enolates; homogeneous cat-
alysis; nitrogen heterocycles; palladium
Duringthe past decade there has been a growinginterest
in the palladium-catalyzed couplingreactions of aryl
and vinyl halides with enolates and related anions. How- plingof amino-tethered vinyl halides and ketones was
ever, while the reactions of aryl halides have been exten- also accomplished in some cases by usingCs CO3 as
2
sively studied, and it is now possible to introduce an ar- the base, although these reaction conditions were only
omatic unit to a broad range of enolate-type nucleo- suitable for the construction of five-membered ringsys-
philes,[1] the couplingreactions involvingvinyl halides
have received little attention and deal almost exclusive-
ly with the a-alkenylation of ketone enolates.
tems and afforded moderate or low yields.[4b]
Continuingour studies on this palladium chemistry, [8]
we have recently reported that both vinyl and aryl hal-
The first examples of such palladium-catalyzed cou- ides undergo the intramolecular coupling with amino-
plingreactions involvingvinyl halides were reported tethered allylic nitro moieties in the presence of a palla-
by Piers at the beginning of the 1990s, when he describ- dium catalyst and a base, potassium phenoxide beingthe
ed the intramolecular alkenylation of ketone enolates reagent of choice in these reactions.[9]
and then applied the reaction to the synthesis of the di-
terpenoid crinipellin B.[2] Some years later, another ex- more closely at the couplingreactions of vinyl halides
ample of this couplingprocess was reported by Cook in with ketones and test the use of PhOK in order to find
With these precedents in mind, we decided to look
the context of the total synthesis of the alkaloid (þ)- a more efficient catalytic system. Table 1 shows that
vellosimine,[3] and we reported our studies on the syn- the intramolecular couplingof diverse amino-tethered
thesis of nitrogen heterocycles by the Pd(0)-catalyzed vinyl halides and ketones can be successfully accom-
intramolecular couplingof amino-tethered vinyl hal-
plished when usingPhOK as the base (Method A). For
ides and ketone enolates.[4] Later on, Buchwald describ- the sake of comparison, the results obtained previously
ed the intermolecular vinylation of ketone enolates.[5] by usingKO- t-Bu as the base[4b, c] (Method B) have also
Finally, it is worth mentioningthat isolated examples
of the alkenylation reaction have also been reported
been included.
The examples depicted include intramolecular cou-
in the studies of the Pd(0)-catalyzed intermolecular ar- plingprocesses from g-amino, b-amino, and a-amino ke-
ylation of ester[6] and alanine-derived azlactone[7] eno- tones leadingto seven-, six-, and five-membered rings in
lates.
generally good yields. It is noteworthy that the use of
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DOI: 10.1002/adsc.200404148
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Pd-Catalyzed Intramolecular Couplingof Amino-Tethered Vinyl Halides
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[a]
Table 1. Pd-catalyzed intramolecular couplingof vinyl halides and ketones usingPhOK as the base.
Entry
Substrate
Method[b]
Time
Products/yield[c]
1
2
A
3 h
92%[d]
1
B[e]
0.5 h
2
40–50%[f]
3
4
5
6
A
2.5 h
0.75 h
3 h
82%
41%
3
6
B[e]
A
24%
77%
54%
B[g]
0.5 h
7
7
8
A[h]
96 h
5 h
48%
5%
A
70%
9
A
1 h
4 h
89%
10
13
15
B[e]
14
16
41%[i]
11
A
3 h
83%, 16/17 ratio 2.8: 1
12
13
B[e]
A
4 h
3 h
17
32%, 16/17 ratio 1: 1
15%
[a]
For the preparation of substrates and NMR data of the cyclization products, see SupportingInformation.
Method A: KO-t-Bu (2.5 equivs.), PhOH (3 equivs.), Pd(PPh3)4 (0.05 equivs.), THF reflux. Method B: KO-t-Bu (1.5
equivs.), Pd(PPh3)4 (0.2 equivs.), THF reflux.
[b]
[c]
[d]
[e]
[g]
[i]
Yields refer to pure isolated products of reactions on 0.15–0.25 mmol scale.
When the reaction was carried out startingfrom 1.5 mmol of 1, ketone 2 was isolated in 88% yield.
[f]
See Ref.[4b]
See Ref.[4c]
Minor amounts (5%) of a dimeric compound were also isolated.
Pd(PPh3)4 (0.2 equivs.).
[h]
Minor amounts of a dimeric compound (5%) and of the correspondingalkyne (5%) were also isolated.
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Daniel Sole et al.
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PhOK allowed the amount of the palladium catalyst to scope. In this context, it should be noted that the reac-
be reduced to 0.05 equivs., although longer reaction tion conditions developed by Cook for the intramolecu-
times were required in general. Compared to the reac- lar couplingof vinyl iodides and ketones [Pd(OAc) ,
2
tions usingKO- t-Buas the base, both the yields and turn- PPh3, Bu4NBr, K2CO3, DMF-H2O (9:1), 70 0C][3] were
over numbers obtained with PhOK are higher. In fact, unsuccessful at promotingthe couplingeither from vinyl
all substrates could be effectively coupled using bromides 1 and 6, which were recovered unchanged, or
0.05 equivs. of Pd(PPh3)4, except for cyclohexanone 8 from vinyl iodide 3, which afforded 4-(N-benzylamino)-
which required the use of 0.2 equivs. of catalyst for the cyclohexanone as the only reaction product.
reaction to reach completion within a reasonable
As PhOK was so effective in promotingthe Pd-cata-
amount of time (entry 7). Under these reaction condi- lyzed intramolecular a-alkenylation of ketones, we de-
tions, 8 underwent cyclization to give 9 in 48% yield, to- cided to test its utility in the a-alkenylation of other eno-
gether with small amounts of alkene 10, formed by hy- late-type nucleophiles. As shown in Table 2, the intra-
drodehalogenation of the starting material.[10]
molecular alkenylation process was extended to amino-
A comparison of the reactions in entries 3 and 4 illus- esters[6,7,11–13] and aminonitriles.[14] Some examples of
trates the dramatic influence of the base in these cou- Pd-catalyzed intramolecular alkenylations involving
plingprocesses. When KO- t-Bu was used as the base in cyclization at the a-methylene carbons of g-, b-, and a-
the intramolecular couplingfrom
3, considerable amino esters to afford six- and five-membered rings in
amounts of the elimination compound 5 were obtained moderate to good yields are reported (entries 1, 2, and
(entry 4), but this side product was not observed when 4). As already observed in the case of ketone alkenyla-
usingPhOK in spite of the presence of a larger excess
of base (entry 3).
tions leadingto monocyclic compounds (see entries 9–
12 in Table 1), the initially formed annulation products
As shown in entries 8 and 11, b-amino ketones 11 and underwent isomerization to the more stable conjugated
15, which underwent retro-Michael fragmentation as enoates. However, in the ester series the oxidation of
the main reaction when KO-t-Bu was used, reacted un- pyrrolines 23 and 29 to the correspondingpyrroles was
der the new conditions to give the cyclization products not observed. Additionally, pyrrolidine 25 embodying
in high yields. It is especially interesting to note that a quaternary center was obtained, albeit in low yield,
the cyclization reaction of b-amino ketone 11 takes startingfrom an a-substituted ester (entry 3). It is worth
place at a methine position to afford the azaspirocyclic mentioningthat the use of KO- t-Bu as the base instead
ketone 12 in 70% yield (entry 8).
of PhOK in the case of amino esters always resulted in
Additionally, even a-amino ketone 18 (entry 13), the decomposition of the startingmaterial.
which failed to afford the cyclization product with KO-
t-Bu, underwent the intramolecular couplingwhen us-
ingPhOK, although in low yield.
Finally, amino nitriles 30 and 32 underwent the Pd-cat-
alyzed intramolecular a-alkenylation to give pyrrolines
31 and 33, respectively, in moderate or good yields (en-
tries 5 and 6), although longer reaction times were re-
All reactions in Table 1 were conducted usingan ex-
cess of PhOK, which was generated by reaction of 3 quired. As in the ester series, no oxidation to the corre-
equivs. of PhOH and 2.5 equivs. of KO-t-Bu. However, spondingpyrroles was observed.
it should be noted that no more than 1 equiv. of PhOK
The effectiveness of PhOK in the Pd-catalyzed intra-
is required for these cyclization reactions. Thus, treat- molecular alkenylation reactions presented herein is
ment of 1 with 5 mol % of Pd(PPh3)4, 1.3 equivs. of somewhat surprisingsince the p Ka of phenol is consider-
PhOH, and 1 equiv. of KO-t-Bu, gave the bridged ketone ably lower than that of ketones, esters, and nitriles.[15] Al-
2 in 95% yield.
though weak bases (e.g., K3PO4 and Cs2CO3) have been
On the other hand, neither the change of PhOK for used in some Pd-catalyzed arylation[8,16,17] and alkenyla-
PhONa nor the presence of water seems to have any sig- tion[3,4a, b] reactions, PhOK could play an additional role
nificanteffecton the course ofthe reaction. In fact, when in these processes as can be seen in Buchwaldꢁs work,
usingcommercially
available
PhONa·3 H
2O where phenol is used as a catalytic additive in some a-ar-
(1.5 equivs.) instead of PhOK, under essentially the ylation reactions of ketone enolates. In line with Buch-
same reaction conditions, ketone 2 was obtained in waldꢁs proposal,[18] we thought that the intermediacy of
86% yield. On the contrary, the use of commercially a palladium phenoxide complex, which both stabilizes
available PhOLi (2.5 equivs.) resulted in longreaction
times (48 h in refluxingTHF) and afforded a lower yield
(75%) of the cyclization product.
an otherwise unstable intermediate and facilitates the
enolization by coordinatingthe carbonyl group, could
be the most plausible explanation of the key role of
The alkenylation procedure reported here is easy to phenoxide in these reactions.
carry out and no special precautions need to be taken, al-
Further studies directed to extend this methodology
though all cyclization reactions were conducted under to the intramolecular alkenylation and arylation of oth-
an argon atmosphere. The protocol developed in this pa- er stabilized carbanions and to gain deeper insights into
per for the intramolecular a-alkenylation reactions of the role of phenoxide in these processes are in progress
ketones is the most general with respect to the substrate in our laboratory and will be reported in due course.
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[a, b]
Table 2. Pd-catalyzed intramolecular couplingof vinyl halides with esters and nitriles.
Entry
Substrate
Time
Products/yield[c]
1
15 h[d]
42%[e]
74%
2
3
3 h
24 h[d]
24%[f]
4
5
16 h
8 h
79%
70%
49%
6
63 h[d]
[a]
For the preparation of substrates and NMR data of the cyclization products, see SupportingInformation.
KO-t-Bu (2.5 equivs.), PhOH (3 equivs.), Pd(PPh3)4 (0.05 equivs.), THF reflux.
Yields refer to pure isolated products of reactions on 0.15–0.25 mmol scale.
Pd(PPh3)4 (0.1 equiv.).
N-Benzyl-2-pyrrolidinone (19%) was also isolated.
Allylamine 26 (3%) and dimer 27 (5%) were also obtained:
[b]
[c]
[d]
[e]
[f]
CH2Cl2 and washed with saturated aqueous NaHCO3 and
1 N aqueous NaOH. The organic layer was dried and concen-
trated. The residue was purified by flash chromatography
(SiO2, from CH2Cl2 to 98:2 CH2Cl2/MeOH) to give ketone
12; yield: 27 mg(70%).
Experimental Section
Representative Procedure for the Pd-Catalyzed
Intramolecular Coupling of Amino-Tethered Vinyl
Halides with Ketones, Esters, and Nitriles
To a stirred solution of ketone 11 (51 mg, 0.15 mmol) and phe-
nol (42 mg, 0.45 mmol) in freshly distilled THF (5 mL) were
added under argon t-BuOK (0.37 mmol, 0.37 mL of 1 M solu-
tion in tert-butyl alcohol) and Pd(PPh3)4 (9 mg, 0.008 mmol).
The solution was heated at reflux for 5 h. After beingcooled
to room temperature, the reaction mixture was diluted with
Acknowledgements
This research was supported by the MCYT (Spain)through
Grant BQU2001-3551. Thanks are also given to the DURSI
(Catalonia)for Grant 2001SGR-00083.
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References and Notes
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